Phosphorus-containing derivatives of m-amino-phenols



Patented May 12, 1953 UNITED STATE IIPHOSPHORUS-CONIAINING DERIVATIVES F M-AMIINO-PHENOLS' Alexander Lang Morrison and Frank Ratcliiife Atherton, signers to WelwynGarden City, England, as-

Hoffman'mLa Roche Inc., Nutley,

N. J a corporationof New Jersey No Drawing. Application May a, 1950, Serial No. 159,858. In Great Britain May 4, 1949 group containing not more than eight. carbon" atoms (including isoalkyl and oyclohexyl groups), R is an alkyl or alkenyl group containing not more than four carbon atoms or an aralkyl group, e. g. a benzyl group, and X is a monovalent anion. Preferred monovalent anions are the chloride, bromide, iodide and methyl sulphate anions.

The present specification also includes a process for the manufacture of dialkyl phosphates and alkyl alkyl (or aryl) phosphonates of mdimethylaminophenol of the general Formula I wherein m-dimethylaminophenol in the form of an alkali metal derivative is reacted with a dialkyl halogenophosphonate or an alkyl alkyl (or aryl) halogenophosphonite. These compounds can be readily converted into their quaternary salts of general Formula II in a manner which is known per se.

The quaternary compounds of the present invention have an anticholinesterase activity which renders them useful as pharmaceuticals. l

The dialkyl halogenophosphonate or the alkyl alkyl (or aryl) halogenophosphonite used as the reagent for the introduction of the phosphoruscontaim'ng radical into the m-aminophenol is preferably the chloro-compound. such preferred reagents are:

Dimethyl jchlorophosphonate Diethyl chlorophosphonate Di-(n or iso)-propyl chlorophosphonate Methyl methylchlorophosphonite v Ethyl ethylchlorophosphonite Ethyl phenylchlorophosphonite I The following examples illustrate how the process of the invention may be carried into effect.

Examples of m-Dimethylaminophenyl-diethyl phosphate An ethanclic solution of the sodium salt of m-dimethylaminophenol is prepared by adding m-dimethylaminophenol (7.54 g., 0.055 M) to a solution -of sodium ethoxide, made by dissolving metallic sodium- (1.4 g., 0.061 M) in absolute ethanol (80 ml.), maintained in a nitrogen-atmosphere. Diethyl chlorophosphonate (10.51 g., 0.061 M) is added in one portion and the mixture is refluxed with stirrin for two hours. After cooling, the precipitated sodium chloride is filtered and washed with alcohol and the filtrate is evaporated under reduced pressure. I The residual oil is 1 dissolved in carbon tetrachloride (50 ml.) and the solution is washed with sodium I hydroxide solution (3 x 40 m1. normal solution) andwater (3 x 40 ml.) After drying over potassium carbonate, the drying agent is filtered off and the filtrate evaporated under reduced pressure in a water pump. Distilled under mercury diffusion pump vacuum, the product boils at 1l6-120 C./3 x 10- mm. The yield of m-dimethyl aminophenyl-diethyl phosphate is 10.9 g. (='73%), n =1.5112.

EXAMPLE 2 m-Dimethylaminophenyl-di-isopropyl phosphate m-Dimethylaminophenyl di isopropyl phosphate is prepared in a manner similar to that of Example 1 from m-dimethylaminophenol (8.22 g., 0.06 M), sodium (1.65 g., 0.072 M), isopropyl alcohol (80 ml.) and di-isopropyl chlorophosphonate (14.37 g., 0.072 M). It boils at l10-1l4 C./1 x 10* mm. The yield of m-dimethylaminophenyl di isopropyl phosphate is 12.25 g. (=68%) n "=1.5102.

EXAMPLE 3 m-Dimethylamz'nophenyl-dimethyl phosphate m-Dimethylaminophenol (6.85 g.) is dissolved in ethanolic sodium ethoxide (1.25 g. Na; ml.

solved in carbon tetrachloride (ca. 50 ml.) and? the solution extracted three times with N/2 sodium hydroxide and three timesz;withxwazterz The: solution is dried over anhydrous sodiumsulphateand the. carbon tetrachloiiclev evaporated. in

vacuo. Distillation of the residualihrown 011 gives..- e. m--dimethylaminophenyl-dimethyl phosphate as a colorless-oil, in".

the required product, i.

50% yield; 13. P. 120123 C. at 0.05 mm.

EXAMPLE 4 m Dimethylamz'nophenyl dimethylphosphatew methyl-methyl sulphate A: solution of m--dimethyIaminoplienyl'-cli;--

methyl phosphate (1:..85 gr) in drybenzene (60 ml.) and dimethyl. sulphate (1 m1.) is allowed to stand for 30 hours at Ciduring'which. time the methylemethyl sulphate: crystallise's out. Ether is add'edfandjthe. crystals- P1 829 849 C.) are collected. The: yield amounts. to. 66%. Recrystallisation, from alool'lol ethyl. acetate-ether gives colorless plates of m diinethylamiriophenyldimetliylphosphateemethyl methylisulphate;- M. P. 8486 "C.'

EXAMPLE 5 m Dimethylaminoplienyl diethylphosphate methyl -methyl sulpiwte:

induced" tocrystallise'f-rom' alcohol-ethyl acetateether. The yield is M. P. 68-72 C. (deliquescent). Repeated recrystallisations give small colorless needles of m-dimethylaminophenyl-di-isopropyl phosphate methyl-methyl sulphate,.M. P. 82 8.4 C.

EXAMPLE 7 m..-DimethyZaminophenyZ-di-sec-butyl phosphate m-Dimethylaminophenol (6.9 g.) is dissolved in ethanolic" sodium" ethoxide (1.4 g. Na; ml. ethanol) in a nitrogen atmosphere and disecbutyl chlorophosphon'ate (13.7 g.) is added dropwiseoverzBQ minutes. The procedure is as in EX- ampl'e Theyield of m-dimethylaminophenyldij sec butyl phosphate is 62.5%; B. P. 119-124 C. 2122.3 x 111- to.. .8.x-.1()* mm.

EXAMPLE 8 m flimethylaminophenyl dz sec butyl phosphate-methyZ-methyl sulphate A solution of' m-climethylaminophenyl di secbutyl'phosphate(1'.6'5" g;)' in dry benzene" (4' ml.) and dim-ethyl sulphate (0.7- ml.) is allowed to stand-"for 2 days. The preparation proceeds as in Example 4. Hyg'roscopio colorless plates offindimethyl'aminoph-enyl di-sec-butyl phosphatemethyFmethyY sulphate are obtained, M. P. 92 C.

We claim:

1. A compound selectedfrom the group consisting of m-dimethylaminophenyl-di-lower alkyl phosphates and the quaternaryammonium salts thereof.

2. m-Dimethylaminophenyl diethyl phosphate.

3. m Dimethylamlnophenyldimethylphosphate-methyl-meth-yl sulphate.

4. m-Dimethylaminophenyl diethylphosphatemethyl-methyl-sulphate.

5. m-Dimethylaminophenyl-di-isopropyl phosphate methyl-methyl sulphate.

6. m-Dimethylaminophenyl-l-di-sec butyl phosphate-methyl-methyl sulphate.

ALEXANDER;v LANG MQRR'ISON. FRAIIK. ATI-IERTON.

References Citedin the file of this patent FOREIGN! PATENTS."

Number Country" Date Switzerland Maya, 1949 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF M-DIMETHYLAMINOPHENYL-DI-LOWER ALKYL PHOSPHATES AND THE QUATERNARY AMMONIUM SALTS THEREOF. 